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Published online
doi:10.1083/jcb.200610046
The Journal of Cell Biology, Vol. 176, No. 5, 709-718
The Rockefeller University Press, 0021-9525 $30.00
© Ge et al.
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Article

Critical role of the extracellular signal–regulated kinase–MAPK pathway in osteoblast differentiation and skeletal development



Chunxi Ge1,2, Guozhi Xiao4, Di Jiang1,2, and Renny T. Franceschi1,2,3

1 Department of Periodontics and Oral Medicine and 2 Center for Craniofacial Regeneration, University of Michigan School of Dentistry, Ann Arbor, MI 48109
3 Department of Biological Chemistry, University of Michigan School of Medicine, Ann Arbor, MI 48109
4 Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15240

Correspondence to Renny T. Franceschi: rennyf{at}umich.edu

The extracellular signal–regulated kinase (ERK)–mitogen-activated protein kinase (MAPK) pathway provides a major link between the cell surface and nucleus to control proliferation and differentiation. However, its in vivo role in skeletal development is unknown. A transgenic approach was used to establish a role for this pathway in bone. MAPK stimulation achieved by selective expression of constitutively active MAPK/ERK1 (MEK-SP) in osteoblasts accelerated in vitro differentiation of calvarial cells, as well as in vivo bone development, whereas dominant-negative MEK1 was inhibitory. The involvement of the RUNX2 transcription factor in this response was established in two ways: (a) RUNX2 phosphorylation and transcriptional activity were elevated in calvarial osteoblasts from TgMek-sp mice and reduced in cells from TgMek-dn mice, and (b) crossing TgMek-sp mice with Runx2+/– animals partially rescued the hypomorphic clavicles and undemineralized calvaria associated with Runx2 haploinsufficiency, whereas TgMek-dn; Runx2+/– mice had a more severe skeletal phenotype. This work establishes an important in vivo function for the ERK–MAPK pathway in bone that involves stimulation of RUNX2 phosphorylation and transcriptional activity.

Abbreviations used in ths paper: ALP, alkaline phosphatase; BSP, bone sialoprotein; CCD, cleidocranial dysplasia; E, embryonic day; ERK, extracellular signal–regulated kinase; GAP, GTPase-activating protein; MEK, MAPK/ERK; MEK-DN, dominant-negative MEK1; mOG, mouse osteocalcin gene; OCN, osteocalcin; OSE, osteoblast-specific element.


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